The inventors have already disclosed in Publication No. WO93/05052 that a series of compounds having alkylthiophenyl groups have various useful pharmacological functions as pharmaceuticals. Alkylthiophenyl groups are generally introduced into those compounds by reacting bis(alkylthiophenyl) sulfides with various nucleophilic reagents. ##STR2##
The above publication discloses a method according to the above formulae for synthesizing bis(4-alkylthiophenyl) disulfides among disulfides which are used for the above-described purposes. However, such a method of synthesizing disulfides through a Grignard reaction has the drawback that it is difficult to carry out the method on an industrial scale.
Another method of synthesizing bis(4-alkylthiophenyl) disulfides is disclosed in Synth. Commun., 5(3), 173(1975) in which thioanisole is reacted with disulfur dichloride in the presence of silica gel to obtain bis(4-methylthiophenyl) disulfide. However, this method produces a large amount of bis(4-methylthiophenyl) sulfide as a by-product which cannot be easily removed from the disulfide, and it is difficult to obtain high-purity disulfides. Therefore, this method cannot be used for synthesizing disulfides which are raw materials for the above pharmaceutical products.
A method which is capable of producing high-purity bis(4-alkylthiophenyl) disulfides useful as intermediates in synthesis of pharmaceutical products and organic industrial products on an industrial scale has not been known yet. There is thus strong demand for a novel useful production method.
A method of obtaining 4-alkylthiobenzenethiols from alkyl phenyl sulfides through 4-alkylthiobenzenesulfonyl chlorides is also disclosed in Coltect. Czech. Chem. Commun., 29, 2161(1964)., 39, 3338(974)., 47, 1382(1982). However, this method employs reaction using 5 equivalents of chlorosulfuric acid. In the reaction, therefore, excess chlorosulfuric acid must be decomposed by water after completion of reaction. However, this treatment has the drawback that irritant gases and heat are evolved, and a large amount of waste liquid containing acids is produced.
An object of the present invention is to provide an industrial method of producing bis(4-alkylthiophenyl) disulfides useful as intermediates in synthesis of pharmaceutical products and organic industrial products.